CDLD Pilot Project 1: Role of PRMT1 in Regulating mTORC1 Pathway and Fatty Liver Disease

Wenjian Gan – Department of Biochemistry

Gan Lab Webpage

Fatty liver disease (FLD) is characterized by accumulation of excess fat in the liver, which can be classified as two types: non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). As the increasing prevalence of obesity, insulin resistance and other metabolic disorders, NAFLD has become the most prevalent chronic liver disease. Moreover, NAFLD may progress to non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma (HCC). Extensive studies have demonstrated that several signaling pathways play a critical role on NAFLD progression. Among them, the mTOR pathway is the master regulator of cell growth and metabolism, dysregulation of which has been illustrated in many human diseases including metabolic disorders, a major driver of NAFLD.

As posttranslational modifications (PTMs) is the heart of signal transduction, aberrancies in PTM events have been considered as the main causes of mTOR signaling hyperactivation. Notably, arginine methylation is emerging as one of the most common PTMs, which is catalyzed by protein arginine methyltransferases (PRMTs). Among the nine members of the PRMT family in mammals, PRMT1 is the main type I arginine methyltransferase, which regulates a variety of cellular processes including transcription, DNA repair and signaling transduction. Studies implicated that PRMT1 is an important risk factor for liver diseases including NAFLD and HCC. However, the mechanisms by which PRMT1 promotes these liver disorders remain largely unknown.

We have obtained preliminary data showing that: 1) PRMT1 promotes activation of mTORC1 signaling in response to amino acid stimulation by catalyzing asymmetric dimethylation of WDR24; 2) Loss of PRMT1 suppresses glycolysis, lipid metabolism and cell growth. In this proposal, we will dissect the role of PRMT1/WDR24 in liver diseases by accomplishing two specific Aims. In Aim #1, we will elucidate the molecular mechanism by which PRMT1-mediated methylation of WDR24 promotes mTORC1 activation, which will provide evidence for the first time to directly connect PRMT1 and mTORC1 signaling pathway. In Aim #2, we will investigate the physiological functions of PRMT1/WDR24 axis in NAFLD and HCC. We believe that successful completion of proposed studies will not only significantly expand our current understanding of PRMT1/mTORC1-governed liver disease progression, but also provide a molecular basis and rationale for clinical studies on targeting PRMT1 to treat liver diseases including NAFDL and HCC.

Working hypothesis for the Munera lab showing relationship between PRMT1, WDR24, and fatty liver metabolism 
Figure 1: Illustration presenting the model that will be addressed in the proposed specific aims. In specific aim 1 we propose to examine the molecular mechanism through which PRMT1-mediated methylation of WDR24 promotes mTORC1 activation. In specific aim 2 we will investigate the physiological functions of PRMT1/WDR24 axis in NAFLD and HCC..